EP1836187B1 - Derives d'acide 1h-indole-3-carboxylique et utilisation en tant qu'agonistes de ppar - Google Patents

Derives d'acide 1h-indole-3-carboxylique et utilisation en tant qu'agonistes de ppar Download PDF

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EP1836187B1
EP1836187B1 EP05817577A EP05817577A EP1836187B1 EP 1836187 B1 EP1836187 B1 EP 1836187B1 EP 05817577 A EP05817577 A EP 05817577A EP 05817577 A EP05817577 A EP 05817577A EP 1836187 B1 EP1836187 B1 EP 1836187B1
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radical
optionally substituted
formula
radicals
compound
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EP1836187A1 (fr
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Nathalie Adje
Didier Roche
Stéphane YVON
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to 1 H -indole-3-carboxylic acid derivatives that can be used in the treatment of dyslipidaemia, atherosclerosis and diabetes.
  • the invention also relates to pharmaceutical compositions comprising them and to processes for the preparation of these compounds.
  • the invention relates to the use of these compounds for the production of medicaments for the treatment of dyslipidaemia, atherosclerosis and diabetes.
  • peroxisome proliferator-activated receptor PPAR
  • This family of ligand-activated transcription factors modulates numerous aspects of lipid and carbohydrate metabolism, thus having the possibility of attacking several facets of the diabetic phenotype.
  • PPAR alpha PPAR alpha
  • gamma PPAR alpha
  • delta PPAR ⁇ , PPAR ⁇ and PPAR ⁇ , respectively.
  • PPAR ⁇ is involved in stimulating the ⁇ -oxidation of fatty acids.
  • a change transmitted by a PPAR ⁇ in the expression of genes involved in fatty acid metabolism is the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to the liver and the kidneys, which can lead to hepatocarcinogenesis in rodents.
  • the phenomenon of peroxisome proliferation is not encountered in man.
  • PPAR ⁇ is also involved in controlling the levels of HDL cholesterol in rodents and humans. This effect is at least partially based on a transcription regulation transmitted by a PPAR ⁇ of the major HDL apolipoproteins, apo A-1 and apo A-II.
  • the hypotriglyceridaemiant action of fibrates and fatty acids also involves PPAR ⁇ and can be summarised as follows: (i) increased lipolysis and clearance of the remaining particles, due to changes in the levels of lipoprotein lipase and of apo C-III, (ii) stimulation of fatty acid uptake by the cell and its subsequent conversion into acyl-CoA derivatives by induction of a protein for binding fatty acids and acyl-CoA synthase, (iii) induction of the ⁇ -oxidation pathways of fatty acids, (iv) reduction in the synthesis of fatty acids and triglycerides, and finally (v) reduction in the production of VLDL.
  • both the improved catabolism of the triglyceride-rich particles and the reduced secretion of VLDL particles constitute mechanisms that contribute towards the hypolipidaemiant effect of fibrates.
  • Fibric acid derivatives such as clofibrate, fenofibrate, benzafibrate, ciprofibrate, beclofibrate and etofibrate, and also gemfibrozil, each of which are PPAR ⁇ ligands and/or activators, produce a substantial reduction in plasmatic triglycerides and also a certain increase in HDLs.
  • the effects on LDL cholesterol are contradictory and may depend on the compound and/or the dyslipidaemic phenotype. For these reasons, this class of compounds was first used for the treatment of hypertriglyceridaemia (i.e. Fredrickson Type IV and V) and/or mixed hyperlipidaemia.
  • a PPAR ⁇ agonist during its administration to obese adult insulin-resistant rhesus monkeys, caused a dramatic dose-dependent increase in HDL cholesterol in the serum, while at the same time reducing the levels of low-density LDLs, by depleting the triglycerides and the insulin ( Oliver et al., PNAS, (2001), 98, 5306-5311 ).
  • the same publication also showed that the activation of PPAR ⁇ increased the Al cassette binding the ATP inverse transporter of cholesterol and induced a flow of cholesterol specific for apolipoprotein A1.
  • PPAR ⁇ receptor The subtypes of PPAR ⁇ receptor are involved in the activation of the programme of adipocyte differentiation and are not involved in the stimulation of peroxisome proliferation in the liver.
  • PPAR ⁇ 1 and PPAR ⁇ 2 Two known isoforms of PPAR ⁇ protein: PPAR ⁇ 1 and PPAR ⁇ 2, which differ only in the fact that PPAR ⁇ 2 contains 28 additional amino acids at the amino end.
  • the DNA sequences for the human isotypes are described by Elbrecht et al., BBRC, 224, (1996), 431-437 .
  • mice PPAR ⁇ 2 is specifically expressed in the fat cells. Tontonoz et al., Cell, 79, (1994), 1147-1156 , provide proof showing that one physiological role of PPAR ⁇ 2 is to induce adipocyte differentiation.
  • PPAR ⁇ 2 regulates the expression of genes via an interaction with other proteins and binding to hormone response elements, for example in the 5' lateral regions of the response genes.
  • An example of a PPAR ⁇ 2 response gene is the tissue-specific P2 adipocyte gene.
  • peroxisome proliferators comprising vibrates and fatty acids, activate the transcriptional activity of PPAR receptors, only prostaglandin J 2 derivatives have been identified as potential natural ligands of the PPAR ⁇ subtype, which also binds antidiabetic thiazolidinedione agents with high affinity.
  • glitazones exert their effects by binding to receptors of the family of peroxisome proliferator-activated receptors (PPAR), by controlling certain transcription elements in relation with the biological species listed above. See Hulin et al., Current Pharm. Design, (1996), 2, 85-102 .
  • PPAR ⁇ has been imputed as a major molecular target for the glitazone class of insulin sensitisers.
  • glitazone type which are PPAR agonists; have been approved for use in the treatment of diabetes. These are troglitazone, rosiglitazone and pioglitazone, which are all primary or exclusive agonists of PPAR ⁇ .
  • PPAR alpha plus gamma combination dual agonists
  • tesaglitazar alpha, gamma plus delta triple combination
  • glitazones are beneficial in the treatment of NIDDM, a number of serious unfavourable side effects associated with the use of these compounds have been found. The most serious of these was toxicity to the liver, which has resulted in a certain number of deaths. The most serious problems arose in the use of troglitazone, which has recently been removed from the market for toxicity reasons.
  • PPAR gamma full agonists for instance weight gain, anaemia and oedema, which limit their use (rosiglitazone, pioglitazone).
  • PPAR agonists that are not glitazones and do not contain 1,3-thiazolidinedione species, but which modulate the three known subtypes of PPAR, together or separately, to variable degrees (measured by intrinsic power, maximum breadth of functional response or spectrum of changes in gene expression).
  • the inventors have now discovered a novel class of compounds that are partial or full agonists of PPAR ⁇ , with differing degrees of PPAR ⁇ and/or PPAR ⁇ activity.
  • the invention relates to compounds derived from the 1 H -indole-3-carboxylic acid of the formula (1) below: in which:
  • the acids that can be used for the formation of salts of compounds of the formula (1) are mineral or organic acids.
  • the resulting salts are, for example, the hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, dihydrogen phosphates, citrates, maleates, fumarates, trifluoroacetates, 2-naphthalenesulfonates and para -toluenesulfonates.
  • the bases that can be used for the formation of salts of compounds of the formula (1) are organic or mineral bases.
  • the resulting salts are, for example, the salts formed with metals and especially alkali metals, alkaline-earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminium) or with bases, for instance ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol).
  • alkali metals alkaline-earth metals and transition metals
  • bases for instance ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglu
  • the invention especially encompasses the pharmaceutically acceptable salts, but also salts that allow a suitable separation or crystallisation of the compounds of the formula (1), such as the salts obtained with chiral amines or chiral acids.
  • Examples of chiral amines that can be used include quinine, brucine, (S)-1-(benzyloxymethyl)propylamine (III), (-)-ephedrine, (4S,5R)-(+)-1,2,3,4-tetramethyl-5-phenyl-1,3-oxazolidine, (R)-1-phenyl-2- p -tolylethylamine, (S)-phenylglycinol, (-)-N-methylephedrine, (+)-(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol, (S)-phenylglycinol and (S)- ⁇ -methylbenzylamine, or a mixture of two or more thereof.
  • Examples of chiral acids that can be used include (+)-d-di-O-benzoyltartaric acid, (-)-I-di-O-benzoyltartaric acid, (-)-di-O,O'-p-toluyl-I-tartaric acid, (+)-di-O,O'-p-toluyl-d-tartaric acid, ( R )-(+)-malic acid, ( S )-(-)-malic acid, (+)-camphanic acid, (-)-camphanic acid, R -(-)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, ( S )-(+)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, (+)-camphoric acid, (-)-camphoric acid, (S)-(+)-2-phenylpropionic acid, (R)-(-)-2-phenyl
  • the chiral acid is preferably chosen from (-)-di-O,O'-p-toluyl-I-tartaric acid, (+)-di-O,O'-p-toluyl-d-tartaric acid, ( R )-(-)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, ( S )-(+)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, d-tartaric acid and L-tartaric acid, or a mixture of two or more thereof.
  • the invention also encompasses the possible optical isomers, in particular stereoisomers and diastereoisomers, where appropriate, of the compounds of the formula (1), and also mixtures of the optical isomers in any proportions, including racemic mixtures.
  • the compounds of the formula (1) may also be in various tautomeric forms, which are also included in the present invention, alone or as mixtures of two or more thereof, in all proportions.
  • alkyl radical means a linear or branched hydrocarbon-based chain containing from 1 to 10 carbon atoms and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 1-ethylbutyl, 1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl, 5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and 7,7-dimethylo
  • alkyl radicals present as substituents of the compounds of the formula (1) according to the present invention may be optionally substituted by one or more chemical species chosen from:
  • alkylene chain means a divalent radical of linear or branched aliphatic hydrocarbon-based type derived from the alkyl groups defined above by abstraction of a hydrogen atom.
  • Preferred examples of alkylenediyl chains are -(CH 2 ) k - chains in which k represents an integer chosen from 1, 2, 3, 4, 5 and 6, and the chains >CH(CH 3 ), >C(CH 3 ) 2 , -CH 2 -CH(CH 3 )-CH 2 - and -CH 2 -C(CH 3 ) 2 -CH 2 -.
  • alkenyl radical means a linear or branched hydrocarbon-based chain containing from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and advantageously from 2 to 6 carbon atoms, containing one, two or more unsaturations in the form of a double bond, the said chain being optionally substituted by one or more substituents, which may be identical or different, chosen from halogen atoms and trifluoromethyl, trifluoromethoxy, hydroxyl, alkoxy, alkoxycarbonyl, carboxyl and oxo radicals.
  • alkenyl radicals examples include the ethylenyl radical, the propenyl radical, the isopropenyl radical, the but-2-enyl radical, pentenyl radicals and hexenyl radicals.
  • alkynyl radical means a linear or branched hydrocarbon-based chain containing from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and advantageously from 2 to 6 carbon atoms, containing one, two or more unsaturations in the form of a triple bond, the said chain being optionally substituted by one or more substituents, which may be identical or different, chosen from halogen atoms and trifluoromethyl, trifluoromethoxy, hydroxyl, alkoxy, alkoxycarbonyl, carboxyl and oxo radicals.
  • alkynyl radicals examples include the ethynyl radical, the propynyl radical, the but-2-ynyl radical, pentynyl radicals and hexynyl radicals.
  • aryl radical means a monocyclic or polycyclic carbocyclic aromatic radical containing from 6 to 18 carbon atoms and preferably from 6 to 10 carbon atoms.
  • Aryl radicals that may be mentioned include phenyl, naphthyl, anthryl and phenanthryl radicals.
  • the cycloalkyl radical is taken to mean a cyclic hydrocarbon-based radical containing from 4 to 9 carbon atoms, preferably 5, 6 or 7 carbon atoms and advantageously 5 or 6 carbon atoms, optionally containing one or more unsaturations in the form of double and/or triple bonds, the said cycloalkyl radical being optionally substituted by one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl, alkenyl, alkynyl, trifluoromethyl, trifluoromethoxy, hydroxyl, alkoxy, alkoxycarbonyl, carboxyl and oxo radicals.
  • cycloalkyl radicals are cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl and cycloheptadienyl.
  • cycloalkyl radicals are generally monocyclic radicals, but may also be polycyclic, especially bicyclic or tricyclic, optionally containing one or more unsaturations in the form of double bonds.
  • polycyclic cycloalkyl radicals are, for example, tetrahydronaphthyl, perhydronaphthyl, indanyl, bicyclooctyl, bicyclononyl and bicyclodecyl radicals.
  • heterocyclic radicals are monocyclic, bicyclic or tricyclic radicals containing one or more hetero atoms generally chosen from O, S and N, optionally in oxidised form (in the case of S and N), and optionally one or more unsaturations in the form of double bonds. If they are totally saturated, the heterocyclic radicals are said to be aromatic or heteroaryl radicals.
  • At least one of the monocycles constituting the heterocycle contains from 1 to 4 endocyclic hetero atoms and better still from 1 to 3 hetero atoms.
  • the heterocycle consists of one or more monocycles, each of which is 5- to 8-membered.
  • Examples of 5- to 8-membered monocyclic aromatic heterocyclic radicals are the heteroaryl radicals derived, by abstraction of a hydrogen atom, from aromatic heterocycles, such as pyridine, furan, thiophene, pyrrole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.
  • aromatic heterocycles such as pyridine, furan, thiophene, pyrrole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.
  • Preferred aromatic heterocyclic radicals that may be mentioned include pyridyl, pyrimidinyl, triazolyl, thiadiazolyl, oxazolyl, thiazolyl and thienyl radicals.
  • bicyclic heteroaryls in which each monocycle is 5- to 8-membered are chosen from indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridines, pyrazolotriazines (such as pyrazolo-1,3,4-triazine), pyrazolopyrimidine and pteridine.
  • Preferred heteroaryl radicals that may be mentioned include the quinolyl, pyridyl, benzothiazolyl and triazolyl radicals.
  • tricyclic heteroaryls in which each monocycle is 5- to 8-membered are chosen, for example, from acridine, phenazine and carbazole.
  • Saturated or unsaturated, 5- to 8-membered monocyclic heterocycles are the saturated or, respectively, unsaturated derivatives of the aromatic heterocycles mentioned above.
  • aryl and heterocyclic radicals are optionally substituted by one or more of the following radicals G:
  • T is chosen from a halogen atom; (C 6 -C 18 )aryl; (C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy; (C 1 -C 6 )alkoxy(C 6 -C 18 )aryl; nitro; carboxyl; (C 1 -C 6 )alkoxycarboxyl; and T may represent oxo if it substitutes a saturated or unsaturated heterocycle; or alternatively T represents (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkylcarbonyl((C 1 -C 6 )alkyl) n - in which n is 0 or 1.
  • halogen atom means a chlorine, bromine, iodine or fluorine atom, preferably fluorine or chlorine.
  • the ones that are preferred are those for which R 1 represents -O-R' 1 and most particularly those for which R 1 represents -O-R' 1 , R' 1 being a hydrogen atom or an alkyl radical.
  • a first preferred group of compounds of the invention consists of compounds having one or more of the following characteristics, taken separately or as a combination of one, several or all of them:
  • Another even more preferred group of compounds of the invention consists of compounds having one or more of the following characteristics, taken separately or as a combination of one, several or all of them:
  • Another preferred group of compounds of the invention consists of compounds having one or more of the following characteristics, taken separately or as a combination of one, several or all of them:
  • Another even more preferred group of compounds of the invention consists of compounds having one or more of the following characteristics, taken separately or as a combination of one, several or all of them:
  • the substituents on the aryl and heterocyclic radicals are preferably chosen from halogen atoms, preferably fluorine and/or chlorine, and methyl, ethyl, methoxy, phenyl, trifluoromethyl and trifluoromethoxy radicals.
  • heterocyclic radicals are preferentially chosen from thienyl, benzothiophenyl, pyridyl and oxazolyl radicals.
  • the preferred compounds of the formula (1) are those chosen from:
  • the invention also relates to pharmaceutical compositions comprising a pharmaceutically effective amount of at least one compound of the formula (1) as defined above in combination with one or more pharmaceutically acceptable vehicles.
  • compositions can be administered orally in the form of tablets, gel capsules or granules with immediate release or controlled release, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or locally in the form of a solution, cream or gel.
  • a solid composition for oral administration is prepared by adding to the active principle a filler and, where appropriate, a binder, a disintegrant, a lubricant, a dye or a flavour enhancer, and by forming the mixture into a tablet, a coated tablet, a granule, a powder or a capsule.
  • fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide
  • binders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum tragacanth, gelatine, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin.
  • lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened plant oils.
  • the dye can be any dye permitted for use in medicaments.
  • flavour enhancers include cocoa powder, mint in herb form, aromatic powder, mint in oil form, borneol and cinnamon powder. Needless to say, the tablet or granule may be appropriately coated with sugar, gelatine or the like.
  • An injectable form comprising the compound of the present invention as active principle is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffer, a suspending agent, a solubilising agent, a stabiliser, a tonicity agent and/or a preserving agent, and by converting the mixture into a form for intravenous, subcutaneous or intramuscular injection according to a standard process.
  • the injectable form obtained can be freeze-dried via a standard process.
  • suspending agents examples include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxymethyl cellulose and polyethoxylated sorbitan monolaurate.
  • solubilising agents include castor oil solidified with polyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.
  • the stabiliser encompasses sodium sulfite, sodium metasulfite and ether
  • the preserving agent encompasses methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
  • the present invention also relates to the use of a compound of the formula (1) of the invention for the preparation of a medicament for the prevention or treatment dyslipidaemia, atherosclerosis and diabetes.
  • the effective administration doses and posologies of the compounds of the invention intended for the prevention or treatment of a disease, condition or state caused by or associated with modulation of the activity of the PPARs, depends on a large number of factors, for example on the nature of the modulator, the size of the patient, the desired aim of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used and the observations and conclusions of the treating doctor.
  • a possible suitable dosage of the compounds of the formula (1) is between about 0.1 mg/kg and about 100 mg/kg of body weight per day, preferably between about 0.5 mg/kg and about 50 mg/kg of body weight per day, more preferentially between about 1 mg/kg and about 10 mg/kg of body weight per day and more preferably between about 2 mg/kg and about 5 mg/kg of body weight per day of active material.
  • suitable dosages of the compounds of the formula (1) will be between about 1-10 mg and 1000-10 000 mg per day, preferably between about 5-50 mg and 500-5000 mg per day, more preferably between about 10.0-100.0 mg and 100.0-1000.0 mg per day and even more preferentially between about 20.0-200.0 mg and about 50.0-500.0 mg per day of active material comprising a preferred compound.
  • dosage ranges represent total amounts of active material per day for a given patient.
  • the number of administrations per day at which a dose is administered may vary within wide proportions as a function of pharmacokinetic and pharmacological factors, such as the half-life of the active material, which reflects its rate of catabolism and of clearance, and also the minimum and optimum levels of the said active material reached in the blood plasma or other bodily fluids of the patient and which are required for therapeutic efficacy.
  • the present invention also relates to a general process for the preparation of the compounds of the formula (1), starting with ethyl 6-bromo-5-hydroxy-2-methyl-1 H -indole-3-carboxylate, the hydroxyl function of which is subjected to the action of a compound of the formula (2): Br-A-CO 2 (2)
  • the compounds of the formula (1) can also be prepared from ethyl 6-bromo-5-hydroxy-2-methyl-1 H -indole-3-carboxylate, the hydroxyl function of which is protected in a conventional manner, for example by reaction with acetic anhydride, in the presence of pyridine, and the nitrogen atom is then optionally substituted, under the action of a bromide R 3 -Br, as indicated for the production of compound (4) defined above, and the hydroxyl function is then deprotected, in the presence of a base and in an alcohol, for example sodium hydroxide in methanol, so as to obtain the compound of the formula (5):
  • the attachment to the grafted resin (6) can be performed directly on ethyl 6-bromo-5-hydroxy-2-methyl-1 H- indole-3-carboxylate, so as to obtain the bromo derivative of the formula (9):
  • the compounds of the formula (1) in which R 1 represents H can advantageously be obtained by saponification of the corresponding compounds of the formula (1) in which R 1 represents an alkyl radical, or alternatively starting with the compounds of the formula (1 R ), in which R represents an alkyl radical.
  • the saponification can be performed via the action of a base, such as a mineral base chosen from lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate.
  • the molar amount of base to be used generally ranges from 1 to 20 equivalents and preferably from 1 to 12 equivalents depending on the strength of the selected base.
  • the reaction is preferably performed in a solvent of polar protic type and more preferably in a mixture of a lower (C 1 -C 4 ) alkanol and water, such as a mixture of ethanol and water or methanol and water.
  • a solvent of polar protic type and more preferably in a mixture of a lower (C 1 -C 4 ) alkanol and water, such as a mixture of ethanol and water or methanol and water.
  • the reaction temperature advantageously ranges between room temperature and 120°C and better still between 20°C and 100°C, for example between 20°C and reflux.
  • the compound of the formula (6) can readily be obtained by coupling a resin of Wang type, of the formula (10), with an acid of the formula (11), according to the following reaction scheme:
  • optical isomers of the compounds of the formula (1) can be obtained on the one hand via standard techniques for separating and/or purifying isomers known to those skilled in the art, starting with the racemic mixture of the compound of the formula (1).
  • the optical isomers can also be obtained directly via stereoselective synthesis of an optically active starting compound, or via separation or recrystallisation of the optically active salts of the compounds of the formula (1), the salts being obtained with chiral amines or chiral acids.
  • step 1 A mixture of the compound obtained in step 1 (3.63 g; 9.45 mmol), isobutyl bromide (2.6 g; 18.98 mmol) and potassium carbonate (2.68 g; 19.68 mmol) in DMF (20 ml) is heated for 48 hours. A large excess of the halide, of potassium carbonate and of potassium iodide (0.615 mg) is added and the mixture is heated for a further 48 hours. The reaction medium is then poured into a mixture of ice and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and then concentrated.
  • Example 2 A mixture of the compound obtained in Example 1 (82.0 mg; 0.184 mmol), methanol (2 ml) and aqueous 1 N sodium hydroxide (0.265 ml; 0.265 mmol) is stirred overnight at room temperature. The solvents are evaporated off. The residue is dissolved in water and then treated with concentrated hydrochloric acid. After extraction with ethyl ether and drying over sodium sulfate, evaporation gives a white solid (71 mg; 92%).
  • step 2 A mixture composed of the derivative obtained in step 2 (7.81 g; 19.61 mmol) and aqueous 1 N sodium hydroxide (23.5 ml; 23.5 mmol) in methanol (80 ml) is stirred at room temperature for 1 hour. The reaction medium is then poured into dilute hydrochloric acid. The precipitate formed is filtered off, washed and drained by suction (6.65 g; 90%).
  • the organoborane solution (0.957 ml; 0.45 mmol) is added to a mixture of resin obtained in step 4 (227.27 mg), Pd(PPh 3 ) 4 (8.67 mg; 75.0 ⁇ mol) and aqueous 2 M sodium carbonate (94 ⁇ l; 188 ⁇ mol) in DMF (2 ml).
  • the medium is heated at 80°C overnight.
  • the resin is filtered off and washed three times with DMF, then three times with a 1/1 tetrahydrofuran/water mixture, three times with methanol and then three times with methylene chloride and finally dried under vacuum.
  • step 5 The resin obtained in step 5 is treated for 2 hours at room temperature with an 8/2 mixture of methylene chloride/trifluoroacetic acid (2 ml).
  • the medium is filtered and the resin is then washed with methylene chloride.
  • the filtrate is concentrated to dryness (10 mg).
  • the resin is then treated again for 2 hours with a 1/1 mixture of methylene chloride/trifluoroacetic acid.
  • the resin is filtered off and washed twice with DMF, three times with a 1/1 tetrahydrofuran/water mixture, three times with tetrahydrofuran (THF) and three times with methanol and finally dried under vacuum (3.37 g, theory: 3.52 g).
  • the resin is filtered off and washed three times with DMF (2 ml), three times with 1/1 THF/H 2 O, three times with THF, three times with methanol and three times with methylene chloride and finally dried under vacuum.
  • the resin obtained is treated with an 8/2 mixture of methylene chloride/trifluoroacetic acid (1.5 ml) for 1.5 hours at room temperature.
  • the resin suspended in methylene chloride (1 ml) is then treated with a 6/4 mixture of methylene chloride/trifluoroacetic acid (2 ml) for 1 hour at room temperature.
  • the measurement of the PPAR activation was performed according to a technique described by Lehmann et al. (J. Biol. Chem., 270, (1995), 12953-12956 ).
  • CV-1cells (monkey kidney cells) are cotransfected with an expression vector for the chimeric protein PPAR ⁇ -Gal4 and with a "reporter" plasmid that allows expression of the luciferase gene placed under the control of a promoter comprising Gal4 response elements.
  • the cells are seeded in 96-well microplates and cotransfected using a commercial reagent with the reporter plasmid (pG5-tk-pGL3) and the expression vector for the chimeric protein (PPAR ⁇ -Gal4). After incubation for 4 hours, whole culture medium (comprising 10% foetal calf serum) is added to the wells. After 24 hours, the medium is removed and replaced with whole medium comprising the test products. The products are left in contact with the cells for 18 hours. The cells are then lysed and the luciferase activity is measured using a luminometer. A PPAR ⁇ activation factor can then be calculated by means of the activation of the expression of the reporter gene induced by the product (relative to the control cells that have received no product).
  • whole culture medium comprising 10% foetal calf serum
  • the transactivation test using the expression of a chimeric protein Gal-4-PPAR ⁇ makes it possible to determine also whether an agonist functions as a "full” agonist or as a partial" agonist this system.
  • An agonist is "partial" in this system if it induces a weaker response, i.e. it has lower efficacy, than rosiglitazone, which is a “full” agonist.
  • the transactivation obtained at the plateau with a partial agonist will be between 20% and 50% of the maximum response (efficacy) at the plateau of rosiglitazone.
  • Maximum stimulation of the PPAR ⁇ chimeric protein obtained with rosiglitazone Concentration to reach the maximum stimulation of the PPAR ⁇ chimeric protein 31 24% 1 ⁇ M

Claims (13)

  1. Composé de formule (1):
    Figure imgb0083
     dans laquelle :
    R 1 représente -O-R'1 ou -NR'1R"1, avec R'1 et R"1, identiques ou différents, étant choisis parmi un atome d'hydrogène, un radical alkyle, un radical alcényle, un radical alcynyle, un radical cycloalkyle, un radical aryle et un radical hétéroaryle ;
    R 2 est choisi parmi :
    • un radical alkyle, alcényle ou alcynyle ;
    • un radical aryle éventuellement substitué et/ou éventuellement condensé sur un noyau monocyclique ou polycyclique, saturé ou insaturé, de 5 à 8 chaînons contenant éventuellement un ou plusieurs hétéroatomes choisis parmi O, N et S, ledit noyau étant lui-même éventuellement substitué, et
    • un radical hétérocyclique monocyclique saturé, insaturé ou aromatique, de 5 à 8 chaînons, éventuellement substitué et contenant un ou plusieurs hétéroatomes choisis parmi O, N et S ;
    R 3 est choisi parmi un atome d'hydrogène et un radical alkyle ; et
    A représente une chaîne alkylène, linéaire ou ramifiée, comportant de 1 à 6 atomes de carbone ;
    où
    alkyle peut éventuellement être substitué par une ou plusieurs espèces chimiques choisies parmi :
    un atome d'halogène ; un radical -O-alkyle ; un radical aryle ; un radical cycloalkyle ; et un radical hétérocyclique ;
    alcényle est une chaîne hydrocarbonée, linéaire ou ramifiée, contenant de 2 à 10 atomes de carbone, comprenant une, deux ou plusieurs insaturations sous forme d'une double liaison, ladite chaîne étant éventuellement substituée par un ou plusieurs substituants, identiques ou différents, choisis parmi des atomes d'halogène et des radicaux trifluorométhyle, trifluorométhoxy, hydroxy, alcoxy, alcoxycarbonyle, carboxyle et oxo ;
    alcynyle est une chaîne hydrocarbonée, linéaire ou ramifiée, contenant de 2 à 10 atomes de carbone, comprenant une, deux ou plusieurs insaturations sous forme d'une triple liaison, ladite chaîne étant éventuellement substituée par un ou plusieurs substituants, identiques ou différents, choisis parmi des atomes d'halogène et des radicaux trifluorométhyle, trifluorométhoxy, hydroxy, alcoxy, alcoxycarbonyle, carboxyle et oxo ;
    cycloalkyle est radical hydrocarboné cyclique, contenant de 4 à 9 atomes de carbone, comprenant éventuellement une ou plusieurs insaturations sous forme de doubles et/ou triples liaisons, ledit radical cycloalkyle étant éventuellement substitué par un ou plusieurs substituants, identiques ou différents, choisis parmi des atomes d'halogène et des radicaux alkyle, alcényle, alcynyle, trifluorométhyle, trifluorométhoxy, hydroxy, alcoxy, alcoxycarbonyle, carboxyle et oxo ;
    aryle est un radical aromatique carbocyclique monocyclique ou polycyclique, contenant de 6 à 18 atomes de carbone ;
    hétéroaryle est un radical monocyclique, bicyclique ou tricyclique contenant un ou plusieurs hétéroatomes généralement choisis parmi O, S et N, éventuellement à l'état oxydé (dans le cas de S et de N), et éventuellement une ou plusieurs insaturations sous forme de doubles liaisons ;
    aryle, hétéroaryle sont éventuellement substitués par un ou plusieurs parmi les radicaux G suivants :
    trifluorométhyle ; trifluorométhoxy ; styryle ; atome d'halogène ; radical hétérocyclique aromatique monocyclique, bicyclique ou tricyclique contenant un ou plusieurs hétéroatomes choisis parmi O, N et S; et éventuellement substitué par un ou plusieurs radicaux T tels que définis ci-dessous ; groupement Hét-CO- dans lequel Hét représente un radical hétérocyclique aromatique tel que défini ci-dessus, éventuellement substitué par un ou plusieurs radicaux T ; une chaîne alkylène en C1-C6 ; une chaîne alkylènedioxy en C1-C6; nitro ; cyano ; (C1-C10)-alkyle; (C1-C10)alkylcarbonyle ; (C1-C10)alcoxycarbonyl-A- où A représente (C1-C6)alkylène, (C2-C6)alcénylène ou une liaison ; (C3-C10)cycloalkyle; trifluorométhoxy ; di(C1-C10)alkylamino; (C1-C10)alcoxy-(C1-C10)alkyle ; (C1-C10)alcoxy; (C6-C18)aryle éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)aryl-(C1-C10)alcoxy-(CO)n- où n vaut 0 ou 1, et aryle est éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)aryloxy-(CO)n- où n vaut 0 ou 1 et aryle est éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)arylthio où aryle est éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)aryloxy-(C1-C10)alkyl-(CO)n- où n vaut 0 ou 1 et aryle est éventuellement substitué par un ou plusieurs radicaux T ; un hétérocycle, saturé ou insaturé, monocyclique de 5 à 8 chaînons contenant un ou plusieurs hétéroatomes choisis parmi O, N et S, éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)aryl-carbonyle éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)arylcarbonyl-B-(CO)n- où n vaut 0 ou 1 ; B représente (C1-C6)alkylène ou (C2-C6)alcénylène et aryle est éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)aryl-C-(CO)n- où n vaut 0 ou 1, C représente (C1-C6)alkylène ou (C2-C6)alcénylène et aryle est éventuellement substitué par un ou plusieurs radicaux T ; (C6-C18)aryle condensé sur un hétérocycle saturé ou insaturé tel que défini ci-dessus éventuellement substitué par un ou plusieurs radicaux T ; et (C2-C10)alcynyle ;
    T est un atome d'halogène ; (C6-C18)aryle; (C1-C6)alkyle; (C1-C6)alcoxy; (C1-C6)alcoxy-(C6-C18)aryle; nitro ; carboxyle ; (C1-C6)alcoxycarboxyle ; et T peut représenter oxo dans le cas où il substitue un hétérocycle saturé ou insaturé ; ou bien T représente (C1-C6)alcoxycarbonyl-(C1-C6)alkyle; ou (C1-C6)-alkylcarbonyl-((C1-C6)alkyle)n- où n vaut 0 ou 1 ;
    leurs éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  2. Composé selon la revendication 1, possédant une ou plusieurs des caractéristiques suivantes, prises indépendamment ou en combinaison de une, plusieurs ou de la totalité d'entre elles :
    R1 représente -O-R'1, R'1 étant choisi parmi un atome d'hydrogène et un radical alkyle ;
    R2 représente un radical alkyle éventuellement substitué par un radical -O-alkyle, aryle ou cycloalkyle, ou bien représente un radical aryle éventuellement substitué, ou encore un radical hétérocyclique éventuellement substitué ;
    R3 est choisi parmi un atome d'hydrogène et un radical alkyle éventuellement substitué par un radical -O-alkyle, aryle ou cycloalkyle ; et
    A représente une chaîne alkylène, linéaire ou ramifiée, comportant de 1 à 6 atomes de carbone ;
    leurs éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  3. Composé selon l'une quelconque des revendications précédentes, possédant une ou plusieurs des caractéristiques suivantes, prises indépendamment ou en combinaison de une, plusieurs ou de la totalité d'entre elles :
    R1 représente -O-R'1, R'1 étant choisi parmi un atome d'hydrogène et un radical alkyle comportant de 1 à 6 atomes de carbone ;
    R2 représente un radical alkyle comportant de 1 à 6 atomes de carbone et éventuellement substitué par un radical -O-alkyle comportant de 1 à 6 atomes de carbone, ou substitué par un radical phényle ou un radical cycloalkyle de 5 ou 6 chaînons, ou bien représente un radical phényle éventuellement substitué, ou encore un radical hétérocyclique éventuellement substitué ;
    R3 est choisi parmi un atome d'hydrogène et un radical alkyle comportant de 1 à 6 atomes de carbone et éventuellement substitué par un radical -O-alkyle comportant de 1 à 6 atomes de carbone, ou substitué par un radical phényle ou un radical cycloalkyle de 5 ou 6 chaînons ; et
    A représente une chaîne alkylène, linéaire ou ramifiée, comportant de 1 à 6 atomes de carbone ;
    leurs éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  4. Composé selon l'une quelconque des revendications précédentes, possédant une ou plusieurs des caractéristiques suivantes, prises indépendamment ou en combinaison de une, plusieurs ou de la totalité d'entre elles :
    R1 représente -O-R'1, R'1 étant choisi parmi un atome d'hydrogène, un radical méthyle et un radical éthyle ;
    R2 représente un radical alkyle comportant de 1 à 6 atomes de carbone et éventuellement substitué par un radical méthoxy ou éthoxy, ou substitué par un radical phényle substitué ou un radical cyclopentyle ou cyclohexyle, ou bien représente un radical phényle éventuellement substitué, ou encore un radical hétérocyclique aromatique, éventuellement substitué, comportant au moins un atome d'azote ;
    R3 est choisi parmi un atome d'hydrogène et un radical alkyle comportant de 1 à 6 atomes de carbone et éventuellement substitué par un radical méthoxy ou éthoxy, ou substitué par un radical phényle substitué ou un radical cyclopentyle ou cyclohexyle ; et
    A représente une chaîne alkylène de formule (CH2)k-, où k représente un entier compris entre 1 et 6, bornes incluses, ou une chaîne -C(CH3)2- ;
    leurs éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  5. Composé selon l'une quelconque des revendications précédentes, possédant une ou plusieurs des caractéristiques suivantes, prises indépendamment ou en combinaison de une, plusieurs ou de la totalité d'entre elles :
    R1 représente un atome d'hydrogène ;
    R2 est choisi parmi les radicaux méthyle, éthyle, propyle et n-hexyle, éventuellement substitués par un radical méthoxy ou éthoxy, ou substitué par un radical phényle substitué, ou par un radical cyclopentyle, ou bien représente un radical phényle éventuellement substitué, ou encore un radical pyridyle éventuellement substitué ;
    R3 est choisi parmi un atome d'hydrogène, un radical méthyle, un radical éthyle, un radical propyle, un radical isopropyle, un radical isobutyle et un radical isopentyle, chacun de ces radicaux étant éventuellement substitué par un radical méthoxy ou éthoxy, ou par un radical phényle substitué ; et
    A représente une chaîne alkylène de formule (CH2)k-, où k représente 1, 2 ou 3, ou une chaîne -C(CH3)2- ;
    leurs éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  6. Composé selon l'une quelconque des revendications précédentes, caractérisé en ce que les substituants des radicaux aryle et hétérocycliques sont choisis parmi des atomes d'halogène, de préférence fluor et/ou chlore, et des radicaux méthyle, éthyle, méthoxy, phényle, trifluorométhyle et trifluorométhoxy,
    ses éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  7. Composé selon l'une quelconque des revendications précédentes, caractérisé en ce que les radicaux hétérocycliques sont choisis parmi des radicaux thiényle, benzothiophényle, pyridyle et oxazolyle,
    ses éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables avec des acides ou des bases.
  8. Composé selon la revendication 1, choisi parmi :
    • le 1-benzyl-5-(3-carboxypropoxy)-2-méthyl-6-pyridin-3-yl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-(3-carboxypropoxy)-1-(4-chlorobenzyl)-2-méthyl-6-pyridin-3-yl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-(1-carboxy-1-méthyléthoxy)-2-méthyl-1-(3-méthylbutyl)-6-pyridin-4-yl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-carboxyméthoxy-6-hexyl-1-isobutyl-2-méthyl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-carboxyméthoxy-6-(3-éthoxypropyl)-1-isobutyl-2-méthyl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-carboxyméthoxy-6-(3-cyclopentylpropyl)-1-(2-méthoxyéthyl)-2-méthyl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-carboxyméthoxy-6-[2-(4-fluorophényl)éthyl]-1-(2-méthoxyéthyl)-2-méthyl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-(3-carboxypropoxy)-6-hexyl-1-(2-méthoxyéthyl)-2-méthyl-1H-indole-3-carboxylate d'éthyle ;
    • le 5-(3-carboxypropoxy)-6-(3-éthoxypropyl)-1-(2-méthoxyéthyl)-2-méthyl-1H-indole-3-carboxylate d'éthyle ; et
    • le 5-(3-carboxypropoxy)-6-(3-cyclopentylpropyl)-1-(2-méthoxyéthyl)-2-méthyl-1H-indole-3-carboxylate d'éthyle;
    ainsi que parmi les éventuels isomères optiques, formes oxydes, solvats ainsi que sels d'addition pharmaceutiquement acceptables, avec des acides ou des bases, de ces composés.
  9. Procédé de préparation des composés de formule (1), à partir de 6-bromo-5-hydroxy-2-méthyl-1H-indole-3-carboxylate d'éthyle, dont la fonction hydroxy est soumise à l'action d'un composé de formule (2) :

            Br-A-CO2R     (2)

    dans laquelle A est tel que défini selon la revendication 1 et R représente un groupe protecteur de la fonction acide,
    en présence d'une base, en milieu polaire aprotique,
    pour conduire au composé de formule (3) :
    Figure imgb0084
    dans laquelle A et R sont tels que définis précédemment,
    lequel composé de formule (3) dont l'atome d'azote peut éventuellement être substitué, sous l'action d'un bromure R3-Br, où R3 est tel que défini selon la revendication 1, dans des conditions similaires à celles utilisées pour la préparation du composé de formule (3), de manière à obtenir le composé de formule (4) :
    Figure imgb0085
    dans laquelle A, R3 et R sont tels que définis précédemment,
    puis soumis à une réaction où un composé de formule R'-CH=CH-R" (précurseur du radical R2-, le radical R2- pouvant être représenté par le radical R'-CH2-CH-R") est traité par un borane, pour fournir un R2-borane, où R2 est tel que défini pour les composés de formule (1),
    qui est ensuite couplé au composé de formule (3), en présence d'un catalyseur au palladium, en milieu basique, dans un solvant polaire aprotique, pour fournir le composé de formule (1R) :
    Figure imgb0086
    dans laquelle A, R2, R3 et R sont tels que définis précédemment,
    lequel composé de formule (1R) étant ensuite transformé en acide correspondant de formule (1OH) :
    Figure imgb0087
    cas particulier des composés de formule (1) dans laquelle R1 représente un groupement hydroxy,
    et l'acide est éventuellement estérifié, ou converti en amide correspondant, pour former l'ensemble des composés de formule (1), R1 étant différent d'un groupement hydroxy.
  10. Procédé de préparation d'un composé selon l'une des revendications 1 à 8, à partir de 6-bromo-5-hydroxy-2-méthyl-1H-indole-3-carboxylate d'éthyle, dont la fonction hydroxy est protégée puis l'atome d'azote est éventuellement substitué, sous l'action d'un bromure R3-Br, comme indiqué pour l'obtention du composé (4) défini selon la revendication 9, puis la fonction hydroxy est dé-protégée, en milieu basique, et en présence d'un alcool, de manière à obtenir le composé de formule (5) :
    Figure imgb0088
    dans laquelle R3 est tel que défini selon la revendication 1,
    lequel composé de formule (5), dont la synthèse jusqu'au composé de formule (1) est poursuivie par une technique de synthèse sur résine, par exemple de type Wang greffée, et correspondant à la formule (6) :
    Figure imgb0089
    dans laquelle A est tel que défini selon la revendication 1 et
    Figure imgb0090
    représente le support résine,
    qui, mise au contact du composé (5), en milieu basique et solvant polaire aprotique, en présence d'iodure de potassium, conduit au composé de formule (7) :
    Figure imgb0091
    dans laquelle A, R3 et
    Figure imgb0092
    sont tels que définis précédemment,
    dont l'atome de brome est remplacé par le substituant R2, dans les mêmes conditions opératoires que celles décrites selon la revendication 9 pour l'obtention du composé de formule (1R), conduisant ainsi au composé de formule (8) :
    Figure imgb0093
    dans laquelle A, R2, R3 et
    Figure imgb0094
    sont tels que définis précédemment,
    qui est ensuite décroché du support résine, de façon à fournir le composé de formule (1OH) décrit selon la revendication 9, puis le cas échéant, est estérifié ou converti en amide correspondant, pour former l'ensemble des composés de formule (1), R1 étant différent d'un groupement hydroxy.
  11. Procédé de préparation d'un composé selon l'une des revendications 1 à 8, dans lequel la fixation sur résine greffée (6) peut être effectuée directement sur le 6-bromo-5-hydroxy-2-méthyl-1H-indole-3-carboxylate d'éthyle, afin d'obtenir le dérivé bromé de formule (9) :
    Figure imgb0095
    dans laquelle A et
    Figure imgb0096
    sont tels que définis selon la revendication 10,
    lequel dérivé de formule (9) dont l'atome d'azote peut éventuellement être substitué par le radical R3, et l'atome de brome remplacé par le radical R2 (dans un ordre quelconque), selon les techniques respectives de préparation des composés de formules (5) et (8) définis selon la revendication 10.
  12. Composition pharmaceutique comprenant une quantité pharmaceutiquement efficace d'au moins un composé de formule (1) selon l'une quelconque des revendications 1 à 8, ou obtenu par un procédé selon l'une quelconque des revendications 9 à 11, en association avec un ou plusieurs véhicules pharmaceutiquement acceptables.
  13. Utilisation d'un composé de formule (1) selon l'une quelconque des revendications 1 à 8 ou obtenu par un procédé selon l'une des revendications 9 ou 11, pour la préparation d'un médicament destiné à prévenir ou traiter les dyslipidémies, l'athérosclérose et le diabète.
EP05817577A 2005-01-14 2005-12-17 Derives d'acide 1h-indole-3-carboxylique et utilisation en tant qu'agonistes de ppar Not-in-force EP1836187B1 (fr)

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EP1836187A1 (fr) 2007-09-26
CA2594377A1 (fr) 2006-07-20
US7754740B2 (en) 2010-07-13
FR2880889B1 (fr) 2007-04-06
US20080114034A1 (en) 2008-05-15
BRPI0519839A2 (pt) 2009-03-17
FR2880889A1 (fr) 2006-07-21
ATE424394T1 (de) 2009-03-15
JP5042855B2 (ja) 2012-10-03
AU2005324895A1 (en) 2006-07-20
JP2008526902A (ja) 2008-07-24
CA2594377C (fr) 2014-02-18
MX2007008350A (es) 2007-07-25
DE602005013118D1 (de) 2009-04-16
KR20070104353A (ko) 2007-10-25
AU2005324895B2 (en) 2011-08-04
WO2006074789A1 (fr) 2006-07-20
CN101098865A (zh) 2008-01-02
ES2321745T3 (es) 2009-06-10

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